Pharmaceutical compound

ABSTRACT

Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the following formula (I): wherein X 1  is selected from C and N; X 3  and X 5  may be the same or different and each is independently selected from C, N, O and S; Y is selected from N and O; Z is selected from C, N and O; each bond represented by a dotted line may independently be a double bond or a single bond, provided that valencies at each ring atom are maintained and provided that the ring Q contains at least one double bond and provided that the atom N has a double bond; R 3  and R 5  may be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that the number of R 3  groups present is such that the valency of X 3  is maintained, and the number of R 5  groups present is such that the valency of X 5  is maintained; each R 11  and R 12  may be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that the number of R 11  and R 12  groups present is such that the valency of Z is maintained; R 21  is selected from H and a substituted or unsubstituted organic group; R 22  may be present or absent and is selected from H and a substituted or unsubstituted organic group; and Cy is a cyclic organic group.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a 371 national phase application ofinternational application no. PCT/EP2015/068700, filed Aug. 13, 2015,which claims the benefit of GB Application No. 1414730.0, filed Aug. 19,2014; hereby incorporated by reference in its entirety.

The present invention relates to tryptophan-2,3-dioxygenase (TDO) orindoleamine-2,3-dioxygenase (IDO [IDO1 or IDO2]) inhibitors, and inparticular TDO and IDO inhibitors for use in medicine. The inhibitors ofthe invention may be used in pharmaceutical compositions, and inparticular pharmaceutical compositions for treating a cancer, aninflammatory condition, an infectious disease, a central nervous systemdisease or disorder and other diseases, conditions and disorders. Theinvention also relates to methods of manufacture of such inhibitors, andmethods of treatment using such inhibitors.

Tryptophan Metabolism

The kynurenine pathway (KP) is responsible for >95% of the degradationof the essential amino acid tryptophan. The kynurenine pathway fortryptophan metabolism leads to the production of the essential pyridinenucleotide NAD+ and a number of neuroactive metabolites, includingkynurenine (KYN), kynurenic acid (KYNA), the neurotoxic free-radicalgenerator 3-hydroxykynurenine (3-HK), anthranilic acid, 3-HAA, picolinicacid (PIC), and the excitatory N-methyl-D-aspartate (NMDA) receptoragonist and neurotoxin, quinolinic acid (QUIN) (see FIG. 1). Theremaining 5% of tryptophan is metabolised by tryptophan hydroxylase to5-hydroxytryptophan and then further to 5-hydroxytryptamine (serotonin)and melatonin.

Both the depletion of tryptophan and accumulation of immunosuppressivetryptophan catabolites act to supress antigen-specific T-cell andnatural killer cell responses and induce the formation of regulatory Tcells. Because tryptophan catabolism is induced by inflammatorymediators, notably IFN-γ, it is thought to represent an endogenousmechanism that restricts excessive immune responses, thereby preventingimmunopathology. However, there is evidence that in disease states thisfeedback loop may not be beneficial (reviewed in (Munn and Mellor,2013).

IDO/TDO

The first step of tryptophan catabolism is catalysed by either TDO orIDO. Both enzymes catalyze the oxidative cleavage of the 2,3 double bondin the indole ring, converting tryptophan to N-formylkynurenine. This isthe rate-limiting step in tryptophan catabolism by the kynureninepathway (Grohmann et al., 2003; Stone and Darlington, 2002). TDO is ahomotetramer with each monomer having a molecular mass of 48 kDa,whereas IDO has a molecular mass of 45 kDa and a monomeric structure(Sugimoto et al., 2006; Thackray et al., 2008; Zhang et al., 2007).Despite mediating the same reaction, TDO and IDO are structurallydistinct, sharing only 10% homology mainly within the active site(Thackray et al., 2008).

TDO is expressed at high levels in the liver and is responsible forregulating systemic tryptophan levels. TDO is not induced or regulatedby signals from the immune system, however TDO expression can be inducedby tryptophan or corticosteroids (Miller et al., 2004; Salter andPogson, 1985). More recently, TDO has been found to be expressed in thebrain, where it regulates the production of neuroactive tryptophanmetabolites such as kynurenic acid and quinolinic acid (Kanai et al.,2009).

IDO is the predominant tryptophan catabolising enzyme extra hepaticallyand is found in numerous cells, including macrophages, microglia,neurons and astrocytes (Guillemin et al., 2007; Guillemin et al., 2001;Guillemin et al., 2003; Guillemin et al., 2005). IDO transcription isstringently controlled, responding to specific inflammatory mediators.The mouse and human IDO gene promoters contain multiple sequenceelements that confer responsiveness to type I (IFN-α/β) and, morepotently, type II (IFN-γ) interferons (Chang et al., 2011; Dai andGupta, 1990; Hassanain et al., 1993; Mellor et al., 2003). Various celltypes, including certain myeloid-lineage cells (monocyte-derivedmacrophages and DCs), fibroblasts, endothelial cells and sometumour-cell lines, express IDO after exposure to IFN-γ (Burke et al.,1995; Hwu et al., 2000; Mellor et al., 2003; Munn et al., 1999; Varga etal., 1996). However, the control of IDO transcription is complex andcell-type specific. IDO activity is found constitutively at thematernal-fetal interface, expressed by human extravillous trophoblastcells (Kudo and Boyd, 2000). Outside of the placenta, functional IDOexpression was reported to be highest in the mouse epididymis, gut(distal ileum and colon), lymph nodes, spleen, thymus and lungs(Takikawa et al., 1986).

Another recent variant enzyme of IDO has been shown to catalyse the sameenzymatic step: indoleamine-2,3-dioxygenase 2 (IDO2). However, itsphysiological relevance remains unclear due to its very low activity,the presence of common polymorphisms that inactivate its enzymaticactivity in approximately half of all Caucasians and Asians, and thepresence of multiple splice variants (Lob et al., 2008; Meininger etal., 2011; Metz et al., 2007).

IDO-deficient mice are at a gross level phenotypical normal (Mellor etal., 2003), however, they are slightly more prone to induction ofautoimmunity and stimulation of the innate immune system. IDO −/−knockout mice also display enhanced inflammatory-mediated coloncarcinogenesis and exhibit resistance to inflammation-driven lung andskin cancers (Chang et al., 2011; Yan et al., 2010).

The TDO −/− knockout mouse appears phenotypically normal. However, theTDO knockout mice have a 9-fold increase in the plasma concentration ofL-Trp, while IDO −/− knockout mice had WT levels of L-Trp, this suggeststhat TDO and not IDO regulates systemic Trp. TDO ablation increases Trpin the brain as well as serotonin (5-HT) and is therefore a modulator ofanxiety related behaviour (Kanai et al., 2009). TDO also plays a role inthe maintenance of brain morphology in adult mice as TDO −/− mice showincreased neurogenesis in the hippocampus and subventricular zone duringadulthood (Funakoshi et al., 2011).

Immuno-Modulation: Tryptophan Depletion and Kynurenine Accumulation

Immunoregulation by tryptophan metabolism modulates the immune system bydepletion of the TDO/IDO substrate (tryptophan) in the microenvironmentand the accumulation of products such as kynurenine.

Effector T cells are particularly susceptible to low tryptophanconcentrations, therefore, depletion of the essential amino acidtryptophan from the local microenvironment resulting in effector T-cellanergy and apoptosis. The depletion of tryptophan is detected by thegeneral control non-derepressible-2 kinase (GCN2) (Munn et al., 2005).The activation of GCN2 triggers a stress-response program that resultsin cell-cycle arrest, differentiation, adaptation or apoptosis. T cellslacking GCN2 in mice are not susceptible to IDO-mediated anergy bymyeloid cells, including dendritic cells in tumor-draining lymph nodes(Munn et al., 2005).

Tryptophan metabolites such as kynurenine, kynurenic acid,3-hydroxy-kynurenine, and 3-hydroxy-anthranilic acid suppress T-cellfunction and are capable of inducing T-cell apoptosis. Recent studieshave shown that the aryl hydrocarbon receptor (AHR) is a direct targetof kynurenine (Mezrich et al., 2010; Nguyen et al., 2010; Opitz et al.,2011). The AHR is a basic helix-loop-helix Per-Amt-Sim (PAS) familytranscription factor. As kynurenine accumulates in a tumour, KYN bindsthe AHR, translocates to the nucleus and activates transcription oftarget genes regulated by dioxin-responsive elements (DREs). InT-helper-cells kynurenine results in the generation of regulatory Tcells (Treg).

Pharmacological inhibitors of TDO and/or IDO have utility in a widerange of indications, including Infectious diseases, cancer,neurological conditions and many other diseases.

Infectious Diseases and Inflammation

Infection by bacteria, parasites, or viruses induces a strongIFN-γ-dependent inflammatory response. IDO can dampen protective hostimmunity, thus indirectly leading to increased pathogen burdens. Forexample, IDO activity attenuates Toxoplasma gondii replication in thelung, and the inflammatory damage is significantly decreased by theadministration of the IDO inhibitor 1MT after infection (Murakami etal., 2012). Also, in mice infected with murine leukaemia virus (MuLV),IDO was found to be highly expressed, and ablation of IDO enhancedcontrol of viral replication and increased survival (Hoshi et al.,2010). In a model of influenza infection, the immunosuppressive effectsof IDO could predispose lungs to secondary bacterial infection (van derSluijs., et al 2006). In Chagas Disease, which is caused by theTrypanosoma cruzi parasite, kynurenine is increased in patients andcorrelates with disease severity (Maranon et al., 2013). Therefore, IDOinhibitors could be used to improve the outcomes of patients with a widevariety of infectious diseases and inflammatory conditions. Given therole of TDO in controlling systemic Trp levels, TDO inhibitors couldalso be used to improve the outcomes of patients with a wide variety ofinfectious diseases and inflammatory conditions.

IDO and Immunity to Gut Bacteria

IDO plays a role in regulating mucosal immunity to the intestinalmicrobiota. IDO has been shown to regulate commensal induced antibodyproduction in the gut; IDO-deficient mice had elevated baseline levelsof immunoglobulin A (IgA) and immunoglobulin G (IgG) in the serum andincreased IgA in intestinal secretions. Due to elevated antibodyproduction, IDO deficient mice were more resistant to intestinalcolonization by the gram-negative enteric bacterial pathogen Citrobacterrodentium than WT mice. IDO-deficient mice also displayed enhancedresistance to the colitis caused by infection with C. rodentium(Harrington et al., 2008).

Therefore, pharmacological targeting of IDO activity may represent a newapproach to manipulating intestinal immunity and controlling thepathology caused by enteric pathogens including colitis (Harrington etal., 2008).

HIV Infection

Patients infected with HIV have chronically reduced levels of plasmatryptophan and increased levels of kynurenine, and increased IDOexpression (Fuchs et al., 1990 and Zangerle et al., 2002).

In HIV patients the upregulation of IDO acts to suppress immuneresponses to HIV antigens contributing to the immune evasion of thevirus. HIV triggers high levels of IDO expression when it infects humanmacrophages in vitro (Grant et al., 2000), and simian immunodeficiencyvirus (SIV) infection of the brain in vivo induces IDO expression bycells of the macrophage lineage (Burudi et al., 2002).

The pathogenesis of HIV is characterized by CD4+ T cell depletion andchronic T cell activation, leading ultimately to AIDS (Douek et al.,2009). CD4+ T helper (TH) cells provide protective immunity and immuneregulation through different immune cell functional subsets, includingTH1, TH2, T regulatory (Treg), and TH17 cells. Progressive HIV isassociated with the loss of TH17 cells and a reciprocal increase in thefraction of the immunosuppressive Treg cells. The loss of TH17/Tregbalance is associated with induction of IDO1 by myeloidantigen-presenting dendritic cells (Favre et al., 2010). In vitro, theloss of TH17/Treg balance is mediated directly by the proximaltryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid.Therefore in progressive HIV, induction of IDO contributes to theinversion of the TH17/Treg balance and maintenance of a chronicinflammatory state (Favre et al., 2010). Therefore, IDO inhibitors couldhave utility in addressing the TH17/Treg balance in HIV.

Sepsis-Induced Hypotension

Systemic inflammation such as sepsis is characterized by arterialhypotension and systemic inflammatory response syndrome (Riedemann etal., 2003). The associated increase in circulating pro-inflammatorycytokines, including interferon-γ (IFN-γ), leads to the uncheckedproduction of effector molecules such as reactive oxygen and nitrogenspecies that themselves can contribute to pathology (Riedemann et al.,2003).

The metabolism of tryptophan to kynurenine by IDO expressed inendothelial cells contributes to arterial vessel relaxation and thecontrol of blood pressure (Wang et al., 2010). Infection of mice withmalarial parasites (Plasmodium berghei), and experimental induction ofendotoxemia, caused endothelial expression of IDO, resulting indecreased plasma tryptophan, increased kynurenine, and hypotension.Pharmacological inhibition of IDO increased blood pressure insystemically inflamed mice, but not in mice deficient for IDO orinterferon-γ, which is required for IDO induction. Arterial relaxationby kynurenine was mediated by activation of the adenylate and solubleguanylate cyclase pathways. (Wang et al., 2010). Therefore, inhibitorsof IDO (and TDO, given its role in controlling systemic Trp levels)could have utility in treating sepsis-induced hypotension.

CNS Disorders

In the central nervous system both fates of TRP which act as a precursorto kynurenine and serotonin are pathways of interest and importance.Metabolites produced by the kynurenine pathway have been implicated toplay a role in the pathomechanism of neuroinflammatory andneurodegenerative disorder (summarised in FIG. 2). The first stableintermediate from the kynurenine pathway is KYN. Subsequently, severalneuroactive intermediates are generated. They include kynurenic acid(KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN). 3-HK andQUIN are neurotoxic by distinct mechanisms; 3-HK is a potentfree-radical generator (Hiraku et al., 1995; Ishii et al., 1992;Thevandavakkam et al., 2010), whereas QUIN is an excitotoxicN-methyl-D-aspartate (NMDA) receptor agonist (Schwartz et al., 1983;Stone and Perkins, 1981). KYNA, on the other hand, has neuroprotectiveproperties as an antagonist of excitatory amino acid receptors and afree-radical scavenger (Carpenedo et al., 2001; Foster et al., 1984;Goda et al., 1999; Vecsei and Beal, 1990). Changes in the concentrationlevels of kynurenines can shift the balance to pathological conditions.The ability to influence the metabolism towards the neuroprotectivebranch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA)synthesis, may be one option in preventing neurodegenerative diseases.

In the CNS, the kynurenine pathway is present to varying extents in mostcell types, Infiltrating macrophages, activated microglia and neuronshave the complete repertoire of kynurenine pathway enzymes. On the otherhand, neuroprotective astrocytes and oligodendrocytes lack the enzyme,kynurenine 3-monooxygenase (KMO) and indoleamine 2,3 dioxygenase 1(IDO-1) respectively, and are incapable of synthesizing the excitotoxin,quinolinic acid (QUIN) (Guillemin et al., 2000; Lim et al., 2007). TDOis expressed in low quantities in the brain, and is induced by TRP orcorticosteroids (Salter and Pogson 1985; Miller et al., 2004).

Given the role of TDO and IDO in the pathogenesis of several CNSdisorders as well as the role of TDO in controlling systemic Trp levels,IDO and/or TDO inhibitors could be used to improve the outcomes ofpatients with a wide variety of CNS diseases and neurodegeneration.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is aprogressive and fatal neurodegenerative disease targeting the motorsystem. ALS results in the selective attacking and destruction of motorneurons in the motor cortex, brainstem and spinal cord.

Although multiple mechanisms are likely to contribute to ALS, thekynurenine pathway activated during neuroinflammation is emerging as acontributing factor. Initial inflammation may inflict a nonlethal injuryto motor neurons of individuals with a susceptible genetic constitution,in turn triggering a progressive inflammatory process which activatesmicroglia to produce neurotoxic kynurenine metabolites that furtherdestroy motor neurons.

In the brain and spinal cord of ALS patients large numbers of activatedmicroglia, reactive astrocytes, T cells and infiltrating macrophageshave been observed (Graves et al., 2004; Henkel et al., 2004). Thesecells release inflammatory and neurotoxic mediators, among others IFN-γ,the most potent inducer of IDO (McGeer and McGeer 2002). The neuronaland microglial expression of IDO is increased in ALS motor cortex andspinal cord (Chen et al., 2010). It has been proposed that the releaseof immune activating agents activates the rate-limiting enzyme of theKP, IDO, which generates metabolites such as the neurotoxin QUIN.Therefore, inhibition of IDO would reduce the synthesis of neurotoxicQUIN, which has been clearly implicated in the pathogenesis of ALS.

Huntington's Disease

Huntington's disease (HD) is a genetic autosomal dominantneurodegenerative disorder caused by expansion of the CAG repeats in thehuntingtin (htt) gene. Patients affected by HD display progressive motordysfunctions characterized by abnormality of voluntary and involuntarymovements (choreoathetosis) and psychiatric and cognitive disturbances.In-life monitoring of metabolites within the KYN pathway provide one ofthe few biomarkers that correlates with the number of CAG repeats andhence the severity of the disorder (Forrest et al., 2010). Post mortemvery high levels of QUIN are found located in areas ofneurodegeneration, while striatal glutamatergic neurones, on which QUINacts as an excitotoxin, are a principal class lost in the disease.Importantly, TDO ablation in a Drosophila model of Huntington's diseaseameliorated neurodegeneration (Campesan et al., 2011).

Alzheimer's Disease

Alzheimer's disease (AD) is an age-related neurodegenerative disordercharacterised by neuronal loss and dementia. The histopathology of thedisease is manifested by the accumulation of intracellular β-amyloid(Aβ) and subsequent formation of neuritic plaques as well as thepresence of neurofibrillary tangles in specific brain regions associatedwith learning and memory. The pathological mechanisms underlying thisdisease are still controversial, however, there is growing evidenceimplicating KP metabolites in the development and progression of AD.

It has been shown that Aβ (1-42) can activate primary cultured microgliaand induce IDO expression (Guillemin et al., 2003; Walker et al., 2006).Furthermore, IDO over-expression and increased production of QUIN havebeen observed in microglia associated with the amyloid plaques in thebrain of AD patients (Guillemin et al., 2005). QUIN has been shown tolead to tau hyperphosphorylation in human cortical neurons (Rahman etal., 2009). Thus, overexpression of IDO and over-activation of the KP inmicroglia are implicated in the pathogenesis of AD.

There is also evidence for TDO involvement in Alzheimer's disease. TDOis upregulated in the brain of patients and AD mice models. Furthermore,TDO co-localizes with quinolinic acid, neurofibrillary tangles-tau andamyloid deposits in the hippocampus of AD patients (Wu et al., 2013).Therefore, the kynurenine pathway is over-activated in AD by both TDOand IDO and may be involved in neurofibrillary tangle formation andassociated with senile plaque formation.

Psychiatric Disorders and Pain

Most tryptophan is processed through the kynurenine pathway. A smallproportion of tryptophan is processed to 5-HT and hence to melatonin,both of which are also substrates for IDO. It has long been known thatamongst other effects acute tryptophan depletion can trigger adepressive episode and produces a profound change in mood even inhealthy individuals. These observations link well with the clinicalbenefits of serotonergic drugs both to enhance mood and stimulateneurogenesis.

The co-morbidity of depressive symptoms, implication of the kynureninepathway in inflammation and an emerging link between TDO and theglucocorticoid mediated stress response also implicate a role in thetreatment of chronic pain (Stone and Darlington 2013).

Schizophrenic patients exhibit elevated KYN levels both in CSF and braintissue, particularly the frontal cortex. This has been associated withthe “hypofrontality” observed in schizophrenia. Indeed rodents treatedwith neuroleptics show a marked reduction in frontal KYN levels. Thesechanges have been associated with reduced KMO and 3HAO. Evidenceincludes an association between a KMO polymorphism, elevated CSF KYN andschizophrenia (Holtze et al., 2012). Taken together there is potentialfor manipulations in this pathway to be both pro-cognate andneuroleptic.

Pain and depression are frequently comorbid disorders. It has been shownthat IDO plays a key role in this comorbidity. Recent studies have shownthat IDO activity is linked to (a) decreased serotonin content anddepression (Dantzer et al., 2008; Sullivan et al., 1992) and (b)increased kynurenine content and neuroplastic changes through the effectof its derivatives such as quinolinic acid on glutamate receptors (Heyeset al., 1992).

In rats chronic pain induced depressive behaviour and IDO upregulationin the bilateral hippocampus. Upregulation of IDO resulted in theincreased kynurenine/tryptophan ratio and decreased serotonin/tryptophanratio in the bilateral hippocampus. Furthermore, IDO gene knockout orpharmacological inhibition of hippocampal IDO activity attenuated bothnociceptive and depressive behaviour (Kim et al., 2012).

Since proinflammatory cytokines have been implicated in thepathophysiology of both pain and depression, the regulation of brain IDOby proinflammatory cytokines serves as a critical mechanistic link inthe comorbid relationship between pain and depression through theregulation of tryptophan metabolism.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized byinflammatory lesions in the white matter of the nervous system,consisting of a specific immune response to the myelin sheet resultingin inflammation and axonal loss (Trapp et al., 1999; Owens, 2003).

Accumulation of neurotoxic kynurenine metabolites caused by theactivation of the immune system is implicated in the pathogenesis of MS.QUIN was found to be selectively elevated in the spinal cords of ratswith EAE, an autoimmune animal model of MS (Flanagan et al., 1995). Theorigin of the increased QUIN in EAE was suggested to be the macrophages.QUIN is an initiator of lipid peroxidation and high local levels of QUINnear myelin may contribute to the demyelination in EAE and possibly MS.

Interferon beta 1b (IFN-β1b) induces KP metabolism in macrophages atconcentrations comparable to those found in the sera of IFN-b treatedpatients, this which may be a limiting factor in its efficacy in thetreatment of MS (Guillemin et al., 2001). After IFN-β administration,increased kynurenine levels and kynurenine/tryptophan ratio were foundin the plasma of MS patients receiving IFN-b injection compared tohealthy subjects indicating an induction of IDO by IFN-β (Amirkhani etal., 2005). IFN-β1b, leads to production of QUIN at concentrationssufficient to disturb the ability of neuronal dendrites to integrateincoming signals and kill oligodendrocytes (Cammer 2001). InIFN-β1b-treated patients concomitant blockade of the KP with an IDO/TDOinhibitor may improve its efficacy of IFN-β1b.

Parkinson's Disease

Parkinson's disease (PD) is a common neurodegenerative disordercharacterised by loss of dopaminergic neurons and localizedneuroinflammation.

Parkinson's disease is associated with chronic activation of microglia(Gao and Hong, 2008). Microglia activation release neurotoxic substancesincluding reactive oxygen species (ROS) and proinflammatory cytokinessuch as INF-γ (Block et al., 2007), a potent activator of KP viainduction of IDO expression. KP in activated microglia leads toupregulation of 3HK and QUIN. 3HK is toxic primarily as a result ofconversion to ROS (Okuda et al., 1998). The combined effects of ROS andNMDA receptor-mediated excitotoxicity by QUIN contribute to thedysfunction of neurons and their death (Braidy et al., 2009; Stone andPerkins, 1981). However, picolinic acid (PIC) produced through KPactivation in neurons, has the ability to protect neurons againstQUIN-induced neurotoxicity, being NMDA agonist (Jhamandas et al., 1990).Microglia can become overactivated, by proinflammatory mediators andstimuli from dying neurons and cause perpetuating cycle of furthermicroglia activation microgliosis. Excessive microgliosis will causeneurotoxicity to neighbouring neurons and resulting in neuronal death,contributing to progression of Parkinson's disease. (Zinger et al 2011):Therefore, PD is associated with an imbalance between the two mainbranches of the KP within the brain. KYNA synthesis by astrocytes isdecreased and concomitantly, QUIN production by microglia is increased.

HIV

HIV patients, particularly those with HIV-linked dementia(Kandanearatchi & Brew 2012), often have significantly elevated KYNlevels in CSF. These levels are directly related to the development ofneurocognitive decline and often the presence of sever psychoticsymptoms (Stone & Darlington 2013).

Cancer

It is clear that tumours can induce tolerance to their own antigens.Tryptophan catabolism in cancer is increasingly being recognized as animportant micro-environmental factor that suppresses antitumor immuneresponses. Depletion of tryptophan and accumulation of immunosuppressivetryptophan catabolites such as kynurenine create an immunosuppressivemilieu in tumours and in tumour-draining lymph nodes by inducing T-cellanergy and apoptosis. Such immunosuppression in the tumourmicroenvironment may help cancers evade the immune response and enhancetumorigenicity (reviewed in Adam et al., 2012).

Recently, both TDO and IDO have been implicated in tumour progression.Individually TDO or IDO have been found to be overexpressed in variouscancers, furthermore, several cancers overexpress both TDO and IDO. TDOand IDO mediate immunosuppressive effects through the metabolization ofTrp to kynurenine, triggering downstream signalling through GCN2, mTORand AHR that can affect differentiation and proliferation of T cells.Also, expression of IDO by activated dendritic cells can serve toactivate regulatory T cells (Tregs) and inhibit tumor-specific effectorCD8+ T cells, thereby constituting a mechanism by which the immunesystem can restrict excessive lymphocyte reactivity (reviewed in Plattenet al., 2012).

IDO

Increased expression of IDO has been shown to be an independentprognostic variable for reduced survival in patients with acute myeloidleukemia (AML), small-cell lung, melanoma, ovarian, colorectal,pancreatic, and endometrial cancers (Okamoto et al., 2005; Ino et al.,2006). Indeed, sera from cancer patients have higherkynurenine/tryptophan ratios than sera from normal volunteers (Liu etal., 2010; Weinlich et al., 2007; Huang et al., 2002). The level of IDOexpression was also shown to correlate with the number of tumourinfiltrating lymphocytes in colorectal carcinoma patients (Brandacher etal., 2006).

In preclinical models, transfection of immunogenic tumour cells withrecombinant IDO prevented their rejection in mice (Uyttenhove et al.,2003). While, ablation of IDO expression led to a decrease in theincidence and growth of 7,12-dimethylbenz(a)anthracene-inducedpremalignant skin papillomas (Muller et al., 2008). Moreover, IDOinhibition slows tumour growth and restores anti-tumour immunity(Koblish et al., 2010) and IDO inhibition synergises with cytotoxicagents, vaccines and cytokines to induce potent anti-tumour activity(Uyttenhove et al., 2003; Muller et al., 2005; Zeng et al., 2009).

TDO

TDO is predominantly expressed in the liver and is believed to regulatesystemic Trp concentrations, however, TDO was found to be frequentlyactivated and constitutively expressed in glioma cells. TDO derived KYNwas shown to suppress antitumor immune responses and promote tumor-cellsurvival and motility through the AhR in an autocrine manner (Opitz etal., 2011). It was also shown that TDO is elevated in humanhepatocellular carcinomas and detected sporadically in other cancers. Ina preclinical model, TDO expression prevented rejection of tumor graftsby preimmunized mice. Systemic administration of the TDO inhibitor,LM10, restored the ability of mice to reject TDO-expressing tumors(Pilotte et al., 2012).

Therefore inhibitors of TDO or IDO could have wide ranging therapeuticefficacy in the treatment of cancer. Also dual inhibitors blocking bothTDO and IDO may demonstrate improved clinical efficacy by targeting bothof these key Trp-metabolising enzymes and would also treat a widerpatient population: in a series of 104 human tumor lines of varioushistological types, 20 tumors expressed only TDO, 17 expressing only IDOand 16 expressed both. Therefore, targeting both IDO and TDO would allowreaching 51% of tumors instead of 32% with IDO or 35% with TDO alone(Pilotte et al., 2012). Moreover, given the role of TDO in controllingsystemic Trp levels, TDO inhibitors could also be used to improve theoutcomes of patients with a wide variety of cancers and neoplasticdiseases that do not express TDO.

Inhibition of IDO and/or TDO will dramatically lower kynurenine levels,relieving the brake on the immune system allowing it to attack andeliminate tumours. While there is evidence that a TDO/IDO inhibitorwould be useful as a stand-alone agent, inhibitors of this type would beparticularly effective when used in combination with other cancerimmunotherapies. In fact, upregulation of IDO expression has beenidentified as a mechanism by which tumours gain resistance to the CTLA-4blocking antibody ipilimumab. Ipilimumab blocks the co-stimulatorymolecule CTLA-4, causing tumour-specific T cells to remain in anactivated state.

IDO knockout mice treated with anti-CTLA-4 antibody demonstrate astriking delay in B16 melanoma tumor growth and increased overallsurvival when compared with wild-type mice. Also, CTLA-4 blockadestrongly synergizes with IDO inhibitors to mediate tumour rejection.Similar data was also reported for IDO inhibitors in combination withanti-PD1 and anti-PDL-1 antibodies (Holmgaard et al., 2013).

Agents that will influence an immunosuppressive environment may also berelevant to chimeric antigen receptor T cell therapy (CAR-T) therapiesto enhance efficacy and patient responses.

Other Diseases

Although these effects are defensive strategies to cope with infectionand inflammation, they may have unintended consequences becausekynurenines formed during IDO and TDO-mediated degradation of tryptophancan chemically modify proteins and have been shown to be cytotoxic(Morita et al., 2001; Okuda et al., 1998). In coronary heart disease,inflammation and immune activation are associated with increased bloodlevels of kynurenine (Wirleitner et al., 2003) possibly viainterferon-γ-mediated activation of IDO. In experimental chronic renalfailure, activation of IDO leads to increased blood levels ofkynurenines (Tankiewicz et al., 2003), and in uremic patientskynurenine-modified proteins are present in urine (Sala et al., 2004).Further, renal IDO expression may be deleterious during inflammation,because it enhances tubular cell injury.

General anaesthesia unfortunately mimics many of these effects inducingstress and inflammatory processes. Post anaesthesia cognitivedysfunction has often been correlated with these sequelae. Recentlythese deficits have been shown to be correlated with changes inkynurenine pathway markers, but not cytokines, following cardiac surgeryand in recovering stroke patients (Stone and Darlington 2013).

Cataracts

A cataract is a clouding of the lens inside the eye that leads to adecrease in vision. Recent studies suggest that kynurenines mightchemically alter protein structure in the human lens leading to cataractformation. In the human lens IDO activity is present mainly in theanterior epithelium (Takikawa et al., 1999). Several kynurenines, suchas kynurenine (KYN), 3-hydroxykynurenine (3OHKYN), and3-hydroxykynurenine glucoside (3OHKG) have been detected in the lens;where they were thought to protect the retina by absorbing UV light andtherefore are commonly referred to as UV filters. However, severalrecent studies show that kynurenines are prone to deamination andoxidation to form α,β-unsaturated ketones that chemically react andmodify lens proteins (Taylor et al., 2002). Kynurenine mediatedmodification could contribute to the lens protein modifications duringaging and cataractogenesis. They may also reduce the chaperone functionof α-crystallin, which is necessary for maintaining lens transparency.

Transgenic mouse lines that overexpress human IDO in the lens developedbilateral cataracts within 3 months of birth. It was demonstrated thatIDO-mediated production of kynurenines results in defects in fibre celldifferentiation and their apoptosis (Mailankot et al., 2009). Thereforeinhibition of IDO may slow the progression of cataract formation.

Female Reproductive Health

Endometriosis

Endometriosis, the presence of endometrium outside the uterine cavity,is a common gynaecological disorder, causing abdominal pain, dyspareuniaand infertility. IDO expression was found to be higher in eutopicendometrium from women with endometriosis by microarray analysis (Burneyet al., 2007 and Aghajanova et al., 2011). Furthermore, IDO was shown toenhance the survival and invasiveness of endometrial stromal cells (Meiet al., 2013). Therefore, an IDO/TDO inhibitor could be used as atreatment for endometriosis.

Contraception and Abortion

The process of implantation of an embryo requires mechanisms thatprevent allograft rejection; and tolerance to the fetal allograftrepresents an important mechanism for maintaining a pregnancy. Cellsexpressing IDO in the foeto-maternal interface protect the allogeneicfoetus from lethal rejection by maternal immune responses. Inhibition ofIDO by exposure of pregnant mice to 1-methyl-tryptophan induced a Tcell-mediated rejection of allogeneic concepti, whereas syngeneicconcepti were not affected; this suggests that IDO expression at thefoetal maternal interface is necessary to prevent rejection of thefoetal allograft (Munn et al., 1998). Accumulating evidence indicatesthat IDO production and normal function at the foetal maternal interfacemay play a prominent role in pregnancy tolerance (Durr and Kindler.,2013). Therefore, an IDO/TDO inhibitor could be used as a contraceptiveor abortive agent.

On the above basis, the inventors have determined that a strongrationale exists for the therapeutic utility of drugs which block theactivity of TDO and or IDO, in treating the above-mentioned diseases,conditions and disorders.

WO 2014/081689 discloses compounds useful as inhibitors of IDO, for thetreatment of various diseases. The compounds disclosed comprise a5-membered heterocyclic system, but are significantly different to thecompounds now developed by the inventors. In J. Med. Chem. 2010, 53,1172-1189 (and also in a later paper in J. Med. Chem. 2012), Rohrig etal. discuss “Rational Design of Indoleamine 2,3-dioxygenase Inhibitors”,in particular as potential treatments for cancer. The compoundssuggested could comprise a 5-membered heterocyclic system, but are againsignificantly different to the compounds now discovered by theinventors. Further such compounds have been disclosed in WO2009/132238,WO2009/073620, WO2011/056652, and WO2012/142237, but none disclose thecompounds that the present inventors have now surprisingly developed.

Liu et al. disclose compounds similar to those of the present inventionin Bioorganic & Medicinal Chemistry, vol. 17, 2009, pp. 6279-6285,“Synthesis and biological evaluation of 3,4-diaryl-5-aminoisoxazolederivatives”. The same compounds are also discussed in Wu et al., CancerLetters, vol. 285, 2009, pp. 13-22, “XN05, a novel synthesisedmicrotubule inhibitor, exhibits potent activity against human carcinomacell lines in vitro”. In each case these compounds are disclosed asbeing direct anti-cancer agents due to their high cytotoxicity. IDO andTDO inhibition is not mentioned, and there is no disclosure that thecompounds have TDO or IDO inhibitory activity, or a pharmacologyassociated with a TDO or IDO mechanism.

Demchuk et al., disclose 1,2,3-triazole compounds in Bioorganic &Medicinal Chemistry, vol. 22, 2014, pp. 738-755, “Synthesis andantiproliferative activity of conformationally restricted 1,2,3-triazoleanalogues of combrestastatins in the sea urchin embryo model and againsthuman cancer cell lines”. Published Australian patent application, AU2012 200157, discloses 1,2,4 triazoles. Both of these documents suggestthat these compounds may be used to treat cancer directly, but IDO andTDO inhibition is not mentioned, and there is no disclosure that thecompounds have TDO or IDO inhibitory activity.

Having regard to the above, it is an aim of the present invention toprovide TDO or IDO inhibitors, and in particular TDO and IDO inhibitorsfor use in medicine. It is a further aim to provide pharmaceuticalcompositions comprising such inhibitors, and in particular to providecompounds and pharmaceutical compositions for treating a cancer, aninflammatory condition, an infectious disease, a central nervous systemdisease or disorder and other diseases, conditions and disorders. It isalso an aim to provide compounds methods of synthesis of the compounds.

Accordingly, the present invention provides a tryptophan-2,3-dioxygenase(TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound foruse in medicine, which compound comprises the following formula:

wherein X¹ is selected from C and N; X³ and X⁵ may be the same ordifferent and each is independently selected from C, N, O and S; Y isselected from N and O; Z is selected from C, N and O; each bondrepresented by a dotted line may independently be a double bond or asingle bond, provided that valencies at each ring atom are maintainedand provided that the ring Q contains at least one double bond andprovided that the atom N has a double bond; R³ and R⁵ may be present orabsent and may be the same or different and each is independentlyselected from H and a substituted or unsubstituted organic group,provided that the number of R³ groups present is such that the valencyof X³ is maintained, and the number of R⁵ groups present is such thatthe valency of X⁵ is maintained; each R¹¹ and R¹² may be present orabsent and may be the same or different and each is independentlyselected from H and a substituted or unsubstituted organic group,provided that the number of R¹¹ and R¹² groups present is such that thevalency of Z is maintained; R²¹ is selected from H and a substituted orunsubstituted organic group; R²² may be present or absent and isselected from H and a substituted or unsubstituted organic group; and Cyis a cyclic organic group.

In the present context the dotted line between two atoms indicates thepossible presence of either a single bond or a double bond. Thus, in acase where two atoms are joined by a dotted line, then those atoms arejoined to each other by at least a single bond, but possibly a doublebond in some cases. In all cases, the valencies at each ring atom aremaintained. In this context, the ring atoms are those atoms that formthe ring Q, i.e. the cyclic arrangement of atoms —X¹—C—X³—N—X⁵—.

In the context of the present invention, maintaining the valency meansensuring that an atom has its normal (typically most common) valency inorganic compounds (i.e. 2 for oxygen and sulphur, 3 for nitrogen and 4for carbon). Nitrogen atoms may, in some instances, have 4 bonds, but insuch cases they are typically positively charged such that the compoundmay have a counter-ion. Such compounds are also considered to be part ofthe invention, and in these cases, due to the positive charge, it willbe clear that the nitrogen atom still maintains its normal valency of 3.For the avoidance of doubt, where the number of R groups may varyaccording to the choice of X, Y or Z group, it may vary as follows.

R³ is absent when X³ is N and is double bonded to a ring atom, and whenX³ is O or S; one R³ is present when X³ is N and is not double bonded toa ring atom, or when X³ is C and is double bonded to a ring atom; andtwo R³ are present (which may be the same or different) when X³ is C andis not double bonded to a ring atom.

R⁵ is absent when X⁵ is N and is double bonded to a ring atom, and whenX⁵ is O or S; one R⁵ is present when X⁵ is N and is not double bonded toa ring atom, or when X⁵ is C and is double bonded to a ring atom; andtwo R⁵ are present (which may be the same or different) when X⁵ is C andis not double bonded to a ring atom.

If X¹ is N, then it is single bonded to two ring atoms, since at leastthe Cy group must be present. If X¹ is C, then it may be single bondedto two ring atoms, or may have a double bond to one ring atom. In thelatter case at least a single Cy group is present. In the former case, afurther substituent may be present to preserve the valency of X¹, whichfurther substituent may be H or an organic group, and is typically H orone or the preferred substituents for R³ or R⁵.

The ring atom to which Y is attached is a C atom. This C atom may besingle bonded to two ring atoms, or may have a double bond to one ringatom. In the latter case only a Y substituent is present on the C atom.In the former case, a further substituent may be present to preserve thevalency of the C atom, which further substituent may be H or an organicgroup, and is typically H or one or the preferred substituents for R³ orR⁵.

For the avoidance of doubt, all tautomers of these structures areencompassed by the invention. In particular, all tautomeric forms of the5-membered ring are intended to be included.

Each of R¹¹ and R¹² may be the same or different, provided that when Zis C both R¹¹ and R¹² are present, when Z is N only one of R¹¹ and R¹²is present and when Z is O neither of R¹¹ and R¹² is present. Z may beabsent, or there may be one ZR¹¹R¹² present or two ZR¹¹R¹² groupsseparating the Cy group from the ring Q. In the latter case each Z maybe the same or different, each R¹¹ may be the same or different, andeach R¹² may be the same or different. Typically Z is absent, and whenpresent, Z is typically C. Typically R¹¹ and R¹² are all H.

Each of R²¹ and R²² may be the same or different, provided that when Yis N, both R²¹ and R²² are present and when Y is O only R²¹ is present.Typically Y is N.

In these compounds, and elsewhere herein, in some embodiments any Rgroup may form a ring with any other R group on an adjacent and/orproximal atom, although in most embodiments this is not preferred,except where explicitly stated. Thus, in some embodiments the followingsubstituents may together form a ring; R¹¹ and R¹², R²¹ and R²², R²¹ andR³, and/or R²² and R³.

In addition, the group Cy may form a ring with any proximal R group.Thus the following substituents may together form a ring: Cy and R¹¹, Cyand R¹², Cy and R²¹, Cy and R²², and/or Cy and R⁵. In the context of thepresent invention, an adjacent and/or proximal atom may mean anotheratom directly bonded to an atom (adjacent), or may be two atoms withonly a single atom in between (proximal), or may mean two atoms closeenough sterically to be capable of forming a ring (proximal). PreferablyR groups attached to the same atom do not together form a ring, althoughthis is not excluded.

In the present context the invention includes compounds in which asingle R group on an atom, or two R groups on the same atom, Ruin agroup which is double bonded to that atom. Accordingly, an R group, ortwo R groups attached to the same atom, may together form a ═O group, ora ═C(R′)₂ group (wherein each R′ group is the same or different and is Hor an organic group, preferably H or a straight or branched C₁-C₆ alkylgroup). This is more typical in cases where the R groups are attached toa C atom, such that together they form a C═O group or a C═C(R′)₂ group.Thus is some cases a C ring atom in ring Q may comprise a ═O group, asmay Z, and/or and one or more of R¹¹, R¹², R²¹, R²², R³, R⁵ and Y.

In the present context the part of the structure present in brackets maybe repeated the number of times given by the numbers next to thebrackets (whether regular brackets or square brackets). For example, inthe case of (C(R))_(0,1,2) or [C(R)]_(0,1,2) the C—R group may beabsent, present once i.e. —C(R)—; or present twice i.e. —C(R)—C(R)—.

In the context of the present invention, a compound is considered to bea TDO inhibitor if its presence is capable of preventing, reducing orslowing the conversion of tryptophan into N-formylkynurenine by TDO ascompared to the same conversion in its absence. Similarly, in thecontext of the present invention, a compound is considered to be an IDOinhibitor if its presence is capable of preventing, reducing or slowingthe conversion of tryptophan into N-formylkynurenine by IDO as comparedto the same conversion in its absence. The compounds of the inventionmay be selective TDO inhibitors, or selective IDO inhibitors, or may beinhibitors of both IDO and TDO.

In typical embodiments, the invention provides a compound as definedabove comprising one or other of the following formulae:

where each of the variables has the same meaning as above. Thus, intypical embodiments the compound takes the form of substituted fivemembered heterocyclic compounds wherein the ring Q comprises at leastone nitrogen atom and at least one double bond, and wherein the N atomon the lower left of the five-membered ring has a double bond.

In all of the embodiments, whether above or below, typically the ring Qcomprises at least two double bonds and/or typically the ring Q isaromatic.

In all of the embodiments of this invention (both above and belowherein), the Cy group is not especially limited, provided that it doesnot prevent the TDO or IDO inhibitory function from occurring. In all ofthe embodiments mentioned in connection with this invention, both aboveand in the following, the Cy group is a cyclic organic group. This maycomprise a monocyclic group or a cyclic group comprising two or morefused or joined rings. It may be a heterocyclic ring or a carbocyclicring. The ring may be fully saturated, or may be unsaturated such thatit contains one or more double bonds. The ring may be aliphatic oraromatic. The ring may comprise any number of atoms provided that thatit does not prevent the TDO or IDO inhibitory function from occurring.Typically the ring comprises from 3-10 atoms, 3-9 atoms, 3-8 atoms, 4-9atoms, 5-8 atoms, 5-7 atoms, or 5, 6 or 7 atoms.

Typically Cy comprises a group of the following formula:

wherein X¹⁰ is selected from C and N, and X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ areindependently selected from C, N, O and S (typically wherein X¹⁰ is C);R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ may be present or absent and whenpresent are selected independently from H and an organic group, providedthat the number of R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ groups presentis such that the valency of X¹⁰, X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ ismaintained.

As already mentioned, in the present context the dotted line between twoatoms indicates the possible presence of either a single bond or adouble bond. Thus, in a case where two atoms are joined by a dottedline, then those atoms are joined to each other by at least a singlebond, but possibly a double bond in some cases. In all cases, thevalencies at each ring atom are maintained. In this context, the ringatoms are those atoms that form the ring Cy, i.e. the cyclic arrangementof atoms —X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—.

For the avoidance of doubt, where the number of R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³,R¹⁰⁴ and R¹⁰⁵ groups may vary according to the choice of X¹⁰, X¹¹, X¹²,X¹³, X¹⁴ and X¹⁵ group, it may vary as follows:

R¹⁰⁰ is absent when X¹⁰ is N or when X¹⁰ is C and is double bonded to aring atom; one R¹⁰⁰ is present when X¹⁰ is C and is not double bonded toa ring atom.

R¹⁰¹ is absent when X¹¹ is N and is double bonded to a ring atom, orwhen X¹¹ is O or S; one R¹⁰¹ is present when X¹¹ is N and is not doublebonded to a ring atom, or when X¹¹ is C and is double bonded to a ringatom; two R¹⁰¹ are present when X¹¹ is a C and is not double bonded to aring atom.

R¹⁰² is absent when X¹² is N and is double bonded to a ring atom, orwhen X¹² is O or S; one R¹⁰² is present when X¹² is N and is not doublebonded to a ring atom, or when X¹² is C and is double bonded to a ringatom; two R¹⁰² are present when X¹² is a C and is not double bonded to aring atom.

R¹⁰³ is absent when X¹³ is N and is double bonded to a ring atom, orwhen X¹³ is O or S; one R¹⁰³ is present when X¹³ is N and is not doublebonded to a ring atom, or when X¹³ is C and is double bonded to a ringatom; two R¹⁰³ are present when X¹³ is a C and is not double bonded to aring atom.

R¹⁰⁴ is absent when X¹⁴ is N and is double bonded to a ring atom, orwhen X¹⁴ is O or S; one R¹⁰⁴ is present when X¹¹ is N and is not doublebonded to a ring atom, or when X¹⁴ is C and is double bonded to a ringatom; two R¹⁰⁴ are present when X¹⁴ is a C and is not double bonded to aring atom.

R¹⁰⁵ is absent when X¹⁵ is N and is double bonded to a ring atom, orwhen X¹⁵ is O or S; one R¹⁰⁵ is present when X¹⁵ is N and is not doublebonded to a ring atom, or when X¹⁵ is C and is double bonded to a ringatom; two R¹⁰⁵ are present when X¹⁵ is a C and is not double bonded to aring atom.

In all of the embodiments of this invention (both above and belowherein), the substituents (each of the R groups) are not especiallylimited, provided that they do not prevent the TDO or IDO inhibitoryfunction from occurring. In all of the embodiments mentioned inconnection with this invention, both above and in the following, thesubstituents are selected from H and an organic group. Thus, both aboveand in the following, the terms ‘substituent’ and ‘organic group’ arenot especially limited and may be any functional group or any atom,especially any functional group or atom common in organic chemistry.Thus, ‘substituent’ and ‘organic group’ may have any of the followingmeanings.

The organic group may comprise any one or more atoms from any of groupsIIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P,O, or S atom (e.g. OH, OR, NH₂, NHR, NR₂, SH, SR, SO₂R, SO₃H, PO₄H₂) ora halogen atom (e.g. F, Cl, Br or I) where R is a linear or branchedlower hydrocarbon (1-6 C atoms) or a linear or branched higherhydrocarbon (7 C atoms or more, e.g. 7-40 C atoms).

The organic group preferably comprises a hydrocarbon group. Thehydrocarbon group may comprise a straight chain, a branched chain or acyclic group. Independently, the hydrocarbon group may comprise analiphatic or an aromatic group. Also independently, the hydrocarbongroup may comprise a saturated or unsaturated group.

When the hydrocarbon comprises an unsaturated group, it may comprise oneor more alkene functionalities and/or one or more alkynefunctionalities. When the hydrocarbon comprises a straight or branchedchain group, it may comprise one or more primary, secondary and/ortertiary alkyl groups.

When the hydrocarbon comprises a cyclic group it may comprise anaromatic ring, a non-aromatic ring, an aliphatic ring, a heterocyclicgroup, and/or fused ring derivatives of these groups. The ring may befully saturated, partially saturated, or fully unsaturated. The cyclicgroup may thus comprise a benzene, naphthalene, anthracene,phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene,s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene,azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, pyrrolidine, furan, tetrahydrofuran,2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, isoxazole,furazan, 1,2,4-oxadiazol, 1,3,4-oxadiazole, thiophene, isothiazole,thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine,piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran,tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran,2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran,2-azathiopyran, 3-azathiopyran, 4-azathiopyran, thiane, indole,indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole,7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole,7-azaisoindole, indolizine, 1-azaindolizine, 2-azaindolizine,3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine,8-azaindolizine, 9-azaindolizine, purine, carbazole, carboline,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline,cinnoline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline,7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline,7-azaisoquinoline, pteridine, chromene, isochromene, acridine,phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene,phenoxanthiin, and/or thianthrene, as well as regioisomers of the abovegroups. These groups may generally be attached at any point in thegroup, and also may be attached at a hetero-atom or at a carbon atom. Insome instances particular attachment points are preferred, such as at1-yl, 2-yl and the like, and these are specified explicitly whereappropriate. All tautomeric ring forms are included in thesedefinitions. For example pyrrole is intended to include 1H-pyrrole,2H-pyrrole and 3H-pyrrole.

The number of carbon atoms in the hydrocarbon group is not especiallylimited, but preferably the hydrocarbon group comprises from 1-40 Catoms. The hydrocarbon group may thus be a lower hydrocarbon (1-6 Catoms) or a higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms).The lower hydrocarbon group may be a methyl, ethyl, propyl, butyl,pentyl or hexyl group or regioisomers of these, such as isopropyl,isobutyl, tert-butyl, etc. The number of atoms in the ring of the cyclicgroup is not especially limited, but preferably the ring of the cyclicgroup comprises from 3-10 atoms, such as 3, 4, 5, 6, 7, 8, 9 or 10atoms.

The groups comprising heteroatoms described above, as well as any of theother groups defined above, may comprise one or more heteroatoms fromany of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such asa B, Si, N, P, O, or S atom or a halogen atom (e.g. F, Cl, Br or I).Thus the substituent may comprise one or more of any of the commonfunctional groups in organic chemistry, such as hydroxy groups,carboxylic acid groups, ester groups, ether groups, aldehyde groups,ketone groups, amine groups, amide groups, imine groups, thiol groups,thioether groups, sulphate groups, sulphonic acid groups, sulphonylgroups, and phosphate groups etc. The substituent may also comprisederivatives of these groups, such as carboxylic acid anhydrides andcarboxylic acid halides.

In addition, any substituent may comprise a combination of two or moreof the substituents and/or functional groups defined above.

The invention will now be explained in more detail, by way of exampleonly, with reference to the following Figures.

FIG. 1 shows a schematic diagram of tryptophan catabolism along the KP(from “The Kynurenine Pathway in Brain Tumour Pathogenesis”, Adam etal., 2012, Cancer Res 72:5649-57).

FIG. 2 shows a schematic summary of the involvement of kynurenine in CNSdisorders (from “The kynurenine pathway as a therapeutic target incognitive and neurodegenerative disorders”, Stone and Darlington. Br. J.Pharmacol. 2013 169(6):1211-27.

The invention will now be described in more detail. Firstly a number oftypical general structures of the compounds of the invention will bedescribed.

As has been described, the invention relates to atryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase(IDO) inhibitor compound for use in medicine, which compound comprisesthe following formula:

wherein X¹ is selected from C and N; X³ and X⁵ may be the same ordifferent and each is independently selected from C, N, O and S; Y isselected from N and O; Z is selected from C, N and O; each bondrepresented by a dotted line may independently be a double bond or asingle bond, provided that valencies at each ring atom are maintainedand provided that the ring Q contains at least one double bond andprovided that the atom N has a double bond; R³ and R⁵ may be present orabsent and may be the same or different and each is independentlyselected from H and a substituted or unsubstituted organic group,provided that the number of R³ groups present is such that the valencyof X³ is maintained, and the number of R⁵ groups present is such thatthe valency of X⁵ is maintained; each R¹¹ and R¹² may be present orabsent and may be the same or different and each is independentlyselected from H and a substituted or unsubstituted organic group,provided that the number of R¹¹ and R¹² groups present is such that thevalency of Z is maintained; R²¹ is selected from H and a substituted orunsubstituted organic group; R²² may be present or absent and isselected from H and a substituted or unsubstituted organic group; and Cyis a cyclic organic group.

As has been mentioned, this definition includes compounds in which,where one or two R groups are attached to the same atom, they maytogether form a group which is double bonded to that atom, such as acarbonyl group (═O) or an alkene group (═C(R′)₂) (wherein each R′ groupis the same or different and is H or an organic group, preferably H or astraight or branched C₁-C₆ alkyl group). Accordingly, in someembodiments R³ or R⁵ may be a ═O group.

The ring Q has at least one unsaturated bond between two adjacent ringatoms, but may also have 2 unsaturated bonds, depending upon the bondingbetween the X atoms, the N atom and the C atom in the ring. The ring maybe aromatic in some cases, but non-aromatic rings are not excluded. Alltautomeric forms of ring Q are included.

In typical embodiments, one of X³ and X⁵ is not a C atom. In moretypical embodiments, one or both of X³ and X⁵ is an N atom, i.e. X³ is Nand/or X⁵ is N. In other typical embodiments, one of X³ and X⁵ is an Oatom, i.e. X³ is O or X⁵ is O. When X³ is O, X⁵ may be C or N and whenX⁵ is O, X³ may be C or N.

In typical embodiments both above and below herein, X¹ is a C atom.

In typical embodiments both above and below herein, Z(R¹¹)(R¹²) isabsent.

In typical embodiments both above and below herein, Y is an N atom.

In typical embodiments both above and below herein, Cy is a 5- or 6- or7-membered carbocyclic or heterocyclic ring, which is typicallyaromatic, although aliphatic rings are not excluded.

Thus, in view of the typical embodiments already described, in moretypical embodiments the invention relates to a compound as definedabove, which compound comprises one or other of the following formulae:

wherein, in each case, the substituents Cy, Q, R and X are as defined inany of the above embodiments.

Furthermore, in view of the typical embodiments already described, inmore typical embodiments the invention relates to compound, whichcompound comprises the following formula:

Furthermore, in view of the typical embodiments already described, inmore typical embodiments the invention relates to compound, whichcompound comprises the following formula:

The Cy, R and X groups are in all of the compounds and structures hereinwill now be described in more detail.

As has been mentioned, the number of R substituents on an X or a ringatom will depend on its valency. Thus, it will be apparent in all of theembodiments of the invention, both above and below, that when X or aring atom has three ring bonds (either 3 single bonds or a single bondand a double bond), it will have no substituents if it is N and 1substituent (H or an organic group as defined herein) if it is C, andwhen X or a ring atom has two ring bonds (2 single bonds), it will have1 substituent (H or an organic group as defined herein) if it is N and 2substituents if it is C (each independently chosen from H or an organicgroup as defined herein). Of course, if X is O there will not be anysubstituents.

As has been mentioned, in all of the embodiments of this invention (bothabove and below herein), the substituent is not especially limited,provided that it does not prevent the TDO or IDO inhibitory functionfrom occurring. However, in typical embodiments, the substituents may beselected independently as follows.

R³, and R⁵ are typically each independently selected from H and a groupselected from the following groups:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —Cl₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂Cl₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   an —OH group or a substituted or unsubstituted linear or        branched C₁-C₆ alcohol group (such as —CH₂OH, —CH₂CH₂OH,        —CH(CH₃)CH₂OH, —C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH,        —CH(CH₃)CH₂CH₂OH, —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH,        —C(CH₃)₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);        —a linear or branched C₁-C₆ carboxylic acid group (such as        —COOH, —CH₂COOH, —CH₂CH₂COOH, —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH,        and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu,        —(CO)iBu, —(CO)tBu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂OPr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂CH₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph,        —SO₂-cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aminosulphonyl group (such as        —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr, —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3        or 4)-F-Ph, —NHSO₂-cyclopropyl, —NHSO₂CH₂CH₂OCH₃);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);    -   a saturated or unsaturated, substituted or unsubstituted,        heterocyclic group including an aromatic heterocyclic group        and/or a non-aromatic heterocyclic group (such as pyrrole-1-yl,        pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl,        imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl,        1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl,        pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl,        piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-1-yl, 3-azapiperidine-2-yl,        3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl,        piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl,        pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl,        isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl,        thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl,        thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl,        thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl,        thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,        isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl); and    -   where there are one or two R groups attached to the same atom,        they may together form a group which is double bonded to that        atom, (such as a carbonyl group (═O) or an alkene group        (═C(R′)₂) (wherein each R′ group is the same or different and is        H or an organic group, preferably H or a straight or branched        C₁-C₆ alkyl group)).

More typically R⁵ is independently selected from H and a group selectedfrom the following groups:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂C₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —Cl₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂Cl₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a cyclic C₃-C₈ alkyl group (such as cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl);    -   an —OH group or a substituted or unsubstituted linear or        branched C₁-C₆ alcohol group (such as —CH₂OH, —CH₂CH₂OH,        —CH(CH₃)CH₂OH, —C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,        —CH(CH₃)CH₂CH₂OH, —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH,        —C(CH₃)₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);        —a linear or branched C₁-C₆ carboxylic acid group (such as        —COOH, —CH₂COOH, —CH₂CH₂COOH, —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH,        and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu,        —(CO)iBu, —(CO)tBu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂OPr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂C H₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph, —SO₂—        cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aminosulphonyl group (such as        —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr, —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3        or 4)-F-Ph, —NHSO₂-cyclopropyl, —NHSO₂CH₂CH₂OCH₃);    -   a saturated or unsaturated, substituted or unsubstituted,        non-aromatic heterocyclic group (such as pyrrolidine-1-yl,        pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl,        piperidine-2-yl, piperidine-3-yl, piperidine-4-yl,        2-azapiperidine-1-yl, 2-azapiperidine-3-yl,        2-azapiperidine-4-yl, 3-azapiperidine-1-yl,        3-azapiperidine-2-yl, 3-azapiperidine-4-yl,        3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl,        furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl,        2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl,        2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl,        2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl,        3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl,        4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl,        4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl,        thiolane-3-yl, thiane-2-yl, thiane-3-yl, and thiane-4-yl); and    -   where there are one or two R groups attached to the same atom,        they may together form a group which is double bonded to that        atom, (such as a carbonyl group (═O) or an alkene group        (═C(R′)₂) (wherein each R′ group is the same or different and is        H or an organic group, preferably H or a straight or branched        C₁-C₆ alkyl group)).

More typically, R³ and R⁵ may each be selected independently from: H, asubstituted or unsubstituted C₁-C₆ alkyl group, an —NH₂ group or asubstituted or unsubstituted C₁-C₆ amino group, a substituted orunsubstituted C₁-C₆ alkoxy group, and a nitrile group.

R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ R¹⁰⁴, R¹⁰⁵, R¹¹, and R¹², are each independentlyselected from H and a group selected from the following groups:

-   -   a halogen (such as —F, —Cl, —Br and —I);    -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —CI₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂CI₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   an —OH group or a substituted or unsubstituted linear or        branched C₁-C₆ alcohol group (such as —CH₂OH, —CH₂CH₂OH,        —CH(CH₃)CH₂OH, —C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH,        —CH(CH₃)CH₂CH₂OH, —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH,        —C(CH₃)₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OCH);        —a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid group (such as —COOH, —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu,        —(CO)iBu, —(CO)tBu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂OPr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂C H₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph,        —SO₂-cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aminosulphonyl group (such as        —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr, —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3        or 4)-F-Ph, —NHSO₂-cyclopropyl, —NHSO₂CH₂CH₂OCH₃);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);    -   a saturated or unsaturated, substituted or unsubstituted,        heterocyclic group including an aromatic heterocyclic group        and/or a non-aromatic heterocyclic group (such as pyrrole-1-yl,        pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl,        imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl,        1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl,        pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl,        piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-1-yl, 3-azapiperidine-2-yl,        3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl,        piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl,        pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl,        isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl,        thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl,        thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl,        thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl,        thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,        isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl); and    -   where there are two R groups attached to the same atom, they may        together form a group which is double bonded to that atom, (such        as a carbonyl group (═O) or an alkene group (═C(R′)₂) wherein        each R′ group is the same or different and is H or an organic        group, preferably H or a straight or branched C₁-C₆ alkyl        group).

More typically, R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ R¹⁰⁴, R¹⁰⁵, R¹¹, and R¹², areeach independently selected from H, a halogen (such as —F, —Cl, —Br, and—I), a substituted or unsubstituted C₁-C₆ alkyl group, an —NH₂ group ora substituted or unsubstituted C₁-C₆ amino group, a substituted orunsubstituted C₁-C₆ alkoxy group, and a nitrile group.

R²¹ and R²² are each independently selected from H and a group selectedfrom the following groups:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, and —CH₂CF₃);    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   a substituted or unsubstituted linear or branched C₂-C₆ alcohol        group (such as —CH₂CH₂OH, —CH(CH₃)CH₂OH, —C(CH₃)₂OH,        —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH(CH₃)CH₂CH₂OH,        —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH, —C(CH₃)₂CH₂OH,        —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);    -   a substituted or unsubstituted linear or branched C₂-C₆        carboxylic acid group (such as —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)-i_Pr, —(CO)-n-Bu,        —(CO)-i-Bu, —(CO)-t-Bu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)—1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph,        —SO₂-cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);        and    -   a substituted or unsubstituted saturated or unsaturated,        substituted or unsubstituted, heterocyclic group including an        aromatic heterocyclic group and/or a non-aromatic heterocyclic        group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl,        imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl,        piperidine-2-yl, piperidine-3-yl, piperidine-4-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-2-yl, 3-azapiperidine-4-yl,        3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl,        pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl,        2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl,        3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl,        3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl,        2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl,        3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl,        2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,        3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl,        isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl,        thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl,        thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl,        thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl,        oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,        isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-5-yl).

In some embodiments of the invention (both above and in the following),R²¹ typically comprises a group having one of the following structures:

wherein R²¹¹ is a group selected from H and:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —Cl₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂Cl₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   a substituted or unsubstituted linear or branched C₁-C₆ alcohol        group (such as —CH₂OH, —CH₂CH₂OH, —CH(CH₃)CH₂OH, —C(CH₃)₂OH,        —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH(CH₃)CH₂CH₂OH,        —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH, —C(CH₃)₂CH₂OH,        —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);    -   a substituted or unsubstituted linear or branched C₂-C₆        carboxylic acid group (such as —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂OPr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂C H₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   an aminosulphonyl group (such as —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr,        —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3 or 4)-F-Ph, —NHSO₂-cyclopropyl,        —NHSO₂CH₂CH₂OCH₃);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);        and    -   a saturated or unsaturated, substituted or unsubstituted,        heterocyclic group including an aromatic heterocyclic group        and/or a non-aromatic heterocyclic group (such as pyrrole-1-yl,        pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl,        imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl,        1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl,        pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl,        piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-1-yl, 3-azapiperidine-2-yl,        3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl,        piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl,        pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl,        isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl,        thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl,        thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl,        thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl,        thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,        isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl).

In other embodiments of the invention (both above and in the following),R²¹ and R²² typically comprise a group selected from H and thefollowing:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, and —CH₂CF₃;    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);        and    -   a substituted or unsubstituted saturated or unsaturated,        substituted or unsubstituted, heterocyclic group including an        aromatic heterocyclic group and/or a non-aromatic heterocyclic        group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl,        imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl,        piperidine-2-yl, piperidine-3-yl, piperidine-4-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-2-yl, 3-azapiperidine-4-yl,        3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl,        pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl,        2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl,        3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl,        3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl,        2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl,        3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl,        2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,        3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl,        isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl,        thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl,        thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl,        thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl,        oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,        isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-5-yl).

The Cy group may comprise a monocyclic group or a cyclic groupcomprising two or more fused or joined rings. It may be a heterocyclicring or a carbocyclic ring. The ring may be fully saturated, or may beunsaturated such that it contains one or more double bonds. The ring maybe aliphatic or aromatic. The ring may comprise any number of atomsprovided that that it does not prevent the TDO or IDO inhibitoryfunction from occurring. Typically the ring comprises from 3-10 atoms,3-9 atoms, 3-8 atoms, 4-9 atoms, 5-8 atoms, 5-7 atoms or 5 or 6 or 7atoms.

Thus, in certain embodiments, Cy may be a group of the followingformula:

wherein X¹⁰ is selected from C and N, and X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ areindependently selected from C, N, O and S (typically wherein X¹⁰ is C);each bond represented by a dotted line may independently be a doublebond or a single bond, provided that valencies at each ring atom X¹⁰,X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ are maintained; R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴and R¹⁰⁵ may be present or absent and when present are selectedindependently from H and an organic group, provided that the number ofR¹¹⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ groups present is such that thevalency of X¹⁰, X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ is maintained.

In typical embodiments, where present, R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ andR¹⁰⁵ are selected from H, halogen (such as —F, —Cl, —Br, —I),substituted or unsubstituted C₁-C₆ alkyl, —NH₂ or substituted orunsubstituted C₁-C₆ amino, substituted or unsubstituted C₁-C₆ alkoxy,and nitrile. Typically, where present, at least one of R¹⁰⁰, R¹⁰¹, R¹⁰²,R¹⁰³, R¹⁰⁴ and R¹⁰⁵ is not H, or all of R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ andR¹⁰⁵ are H). Thus in typical embodiments, Cy may be a 5-, 6-, or7-membered ring, most typically a 6-membered ring, and typically anaromatic ring.

In further typical embodiments Cy comprises a group of the followingformula:

wherein X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ are any of the substituents asdefined above or below herein (in certain cases where all of X¹¹, X¹²,X¹³, X¹⁴ and X¹⁵ are C or at least one of X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ isN), and R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ may be present or absent and maybe any of the substituents as defined above or below herein; preferablywherein, where present, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are selectedfrom H, halogen (such as —F, —Cl, —Br, —I), substituted or unsubstitutedC₁-C₆ alkyl, —NH₂ or substituted or unsubstituted C₁-C₆ amino,substituted or unsubstituted C₁-C₆ alkoxy, and nitrile. Typically, wherepresent, at least one of R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ is not H(typically N), or all of R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are H).

Thus, Cy may be selected from the following:

-   -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);        and    -   a saturated or unsaturated, substituted or unsubstituted,        heterocyclic group including an aromatic heterocyclic group        and/or a non-aromatic heterocyclic group (such as pyrrole-1-yl,        pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl,        imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl,        1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl,        pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl,        piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-1-yl, 3-azapiperidine-2-yl,        3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl,        piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl,        pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl,        isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl,        thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl,        thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl,        thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl,        thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,        isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl).

In some preferred embodiments, the invention therefore provides atryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase(IDO) inhibitor compound for use in medicine, which compound comprisesthe following formula:

wherein X¹ is selected from C and N; X³ and X⁵ may be the same ordifferent and each is independently selected from C, N, O and S; Y isselected from N and O; Z is selected from C, N and O; each bondrepresented by a dotted line may independently be a double bond or asingle bond, provided that valencies at each Q ring atom are maintainedand provided that the ring Q contains at least one double bond andprovided that the atom N has a double bond; R³ and R⁵ may be present orabsent and may be the same or different, provided that the number of R³groups present is such that the valency of X³ is maintained, and thenumber of R⁵ groups present is such that the valency of X⁵ ismaintained; each R¹¹ and R¹² may be present or absent and may be thesame or different, provided that the number of R¹¹ and R¹² groupspresent is such that the valency of Z is maintained; and R²² may bepresent or absent provided that the valency of Y is maintained;

and wherein Cy, —YR²¹R²², R³ and R⁵ do not comprise a substituted orunsubstituted indole or indazole group, and preferably wherein Cy,—YR²¹R²², R³ and R⁵ do not comprise a bicyclic group;

and wherein R³ and R⁵ do not comprise a group comprising an atomdouble-bonded to an oxygen atom at an α-, β-, or γ-position to the Qring atom to which the R³ or R⁵ is attached and in which the atomdouble-bonded to an oxygen atom is also bonded to a hetero-atom;

and wherein Cy comprises a group of the following formula:

wherein X¹⁰ is selected from C and N, and X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ areindependently selected from C, N, O and S, preferably wherein X¹⁰ is C,and R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ may be present or absentprovided that the number of R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴ and R¹⁰⁵ groupspresent is such that the valency of X¹⁰, X¹¹, X¹², X¹³, X¹⁴ and X¹⁵ ismaintained;

and wherein R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ R¹⁰⁴, R¹⁰⁵, R¹¹, and R¹², are eachindependently selected from H and a group selected from the followinggroups:

-   -   a halogen (such as —F, —Cl, —Br and —I);    -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —Cl₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂Cl₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   an —OH group or a substituted or unsubstituted linear or        branched C₁-C₆ alcohol group (such as —CH₂OH, —CH₂CH₂OH,        —CH(CH₃)CH₂OH, —C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH,        —CH(CH₃)CH₂CH₂OH, —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH,        —C(CH₃)₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid group (such as —COOH, —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu,        —(CO)iBu, —(CO)tBu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂OPr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂C H₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph,        —SO₂-cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aminosulphonyl group (such as        —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr, —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3        or 4)-F-Ph, —NHSO₂-cyclopropyl, —NHSO₂CH₂CH₂OCH₃);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);    -   a saturated or unsaturated, substituted or unsubstituted,        heterocyclic group including an aromatic heterocyclic group        and/or a non-aromatic heterocyclic group (such as pyrrole-1-yl,        pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl,        imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl,        1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl,        pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl,        piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-1-yl, 3-azapiperidine-2-yl,        3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl,        piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl,        pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl,        isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl,        thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl,        thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl,        thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl,        thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,        isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl);

preferably wherein R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ R¹⁰⁴, R¹⁰⁵, R¹¹, and R¹², areeach independently selected from H, a halogen (such as —F, —Cl, —Br, and—I), a substituted or unsubstituted C₁-C₆ alkyl group, —NH₂ or asubstituted or unsubstituted C₁-C₆ amino group, a substituted orunsubstituted C₁-C₆ alkoxy group, and a nitrile group;

and wherein R²¹ and R²² are each independently selected from H and agroup selected from the following groups:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, and —CH₂CF₃);    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   a substituted or unsubstituted linear or branched C₂-C₆ alcohol        group (such as —CH₂CH₂OH, —CH(CH₃)CH₂OH, —C(CH₃)₂OH,        —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH(CH₃)CH₂CH₂OH,        —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH, —C(CH₃)₂CH₂OH,        —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂OH);    -   a substituted or unsubstituted linear or branched C₂-C₆        carboxylic acid group (such as —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)-i_Pr, —(CO)-n-Bu,        —(CO)-i-Bu, —(CO)-t-Bu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph, —SO₂—        cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);        and    -   a substituted or unsubstituted saturated or unsaturated,        substituted or unsubstituted, heterocyclic group including an        aromatic heterocyclic group and/or a non-aromatic heterocyclic        group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl,        imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl,        piperidine-2-yl, piperidine-3-yl, piperidine-4-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-2-yl, 3-azapiperidine-4-yl,        3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl,        pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl,        2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl,        3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl,        3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl,        2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl,        3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl,        2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,        3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl,        isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl,        thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl,        thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl,        thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl,        oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,        isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-5-yl);

preferably wherein R²¹ and R²² are each a group independently selectedfrom H and the following:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, and —CH₂CF₃;    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);        and    -   a substituted or unsubstituted saturated or unsaturated,        substituted or unsubstituted, heterocyclic group including an        aromatic heterocyclic group and/or a non-aromatic heterocyclic        group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl,        imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl,        piperidine-2-yl, piperidine-3-yl, piperidine-4-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-2-yl, 3-azapiperidine-4-yl,        3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl,        pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl,        2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl,        3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl,        3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl,        2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl,        3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl,        2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,        3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl,        isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl,        thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl,        thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl,        thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl,        oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,        isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-5-yl);

and wherein R³, and R⁵ are typically each independently selected from Hand a group selected from the following groups:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —Cl₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂Cl₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   an —OH group or a substituted or unsubstituted linear or        branched C₁-C₆ alcohol group (such as —CH₂OH, —CH₂CH₂OH,        —CH(CH₃)CH₂OH, —C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH,        —CH(CH₃)CH₂CH₂OH, —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH,        —C(CH₃)₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid group (such as —COOH, —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu,        —(CO)iBu, —(CO)tBu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂Pr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂C H₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph, —SO₂—        cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aminosulphonyl group (such as        —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr, —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3        or 4)-F-Ph, —NHSO₂-cyclopropyl, —NHSO₂CH₂CH₂OCH₃);    -   a substituted or unsubstituted aromatic group (such as Ph-,        2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-,        2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5        or 6)-F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-,        2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂-Ph-, 2,(3,4,5 or        6)-Et₂-Ph-, 2,(3,4,5 or 6)-Pr₂-Ph-, 2,(3,4,5 or 6)-Bu₂-Ph-,        2,(3,4,5 or 6)-(CN)₂-Ph-, 2,(3,4,5 or 6)-(NO₂)₂-Ph-, 2,(3,4,5 or        6)-(NH₂)₂-Ph-, 2,(3,4,5 or 6)-(MeO)₂-Ph-, 2,(3,4,5 or        6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or        5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or        5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-        (CN)₂-Ph-, 3,(4 or 5)-(NO₂)₂-Ph-, 3,(4 or 5)-(NH₂)₂-Ph-, 3,(4 or        5)-(MeO)₂-Ph-, 3,(4 or 5)-(CF₃)₂-Ph-, 2-Me-Ph-, 3-Me-Ph-,        4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-,        4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-,        4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph-, 4-(NO₂)-Ph-, 2-(NH₂)-Ph-,        3-(NH₂)-Ph-, 4-(NH₂)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-,        2-(NH₂—CO)-Ph-, 3-(NH₂—CO)-Ph-, 4-(NH₂—CO)-Ph-, 2-CF₃-Ph-,        3-CF₃-Ph-, 4-CF₃-Ph-, 2-CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-);    -   a saturated or unsaturated, substituted or unsubstituted,        heterocyclic group including an aromatic heterocyclic group        and/or a non-aromatic heterocyclic group (such as pyrrole-1-yl,        pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl,        pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl,        imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl,        1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl,        1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl,        pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl,        pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl,        pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl,        piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl,        2-azapiperidine-3-yl, 2-azapiperidine-4-yl,        3-azapiperidine-1-yl, 3-azapiperidine-2-yl,        3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl,        piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl,        pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl,        isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl,        thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl,        thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl,        2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,        3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,        3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,        4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl,        thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl,        thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,        isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl,        (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl,        (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and        tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl);

preferably wherein R⁵ is independently selected from H and a groupselected from the following groups:

-   -   a substituted or unsubstituted linear or branched C₁-C₆ alkyl        group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and        hexyl);    -   a substituted or unsubstituted linear or branched C₁-C₆        alkyl-aryl group (such as —CH₂Ph, —CH₂(2,3 or 4)F-Ph, —CH₂(2,3        or 4)Cl-Ph, —CH₂(2,3 or 4)Br-Ph, —CH₂(2,3 or 4)I-Ph, —CH₂CH₂Ph,        —CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂Ph, —CH₂CH₂CH₂CH₂CH₂Ph, and        —CH₂CH₂CH₂CH₂CH₂CH₂Ph);    -   a substituted or unsubstituted linear or branched C₁-C₆        halogenated alkyl group (such as —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,        —CF₃, —CCl₃—CBr₃, —Cl₃, —CH₂CF₃, —CH₂CCl₃, —CH₂CBr₃, and        —CH₂CI₃);    -   —NH₂ or a substituted or unsubstituted linear or branched        primary secondary or tertiary C₁-C₆ amine group (such as —NMeH,        —NMe₂, —NEtH, —NEtMe, —NEt₂, —NPrH, —NPrMe, —NPrEt, —NPr₂,        —NBuH, —NBuMe, —NBuEt, —CH₂—NH₂, —CH₂—NMeH, —CH₂—NMe₂,        —CH₂—NEtH, —CH₂—NEtMe, —CH₂—NEt₂, —CH₂—NPrH, —CH₂—NPrMe, and        —CH₂—NPrEt);    -   a substituted or unsubstituted amino-aryl group (such as —NH-Ph,        —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph,        —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph,        —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,        —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or        4)OBu-Ph, —NH-2,(3,4,5 or 6)F₂-Ph, —NH-2,(3,4,5 or 6)Cl₂-Ph,        —NH-2,(3,4,5 or 6)Br₂-Ph, —NH-2,(3,4,5 or 6)I₂-Ph, —NH-2,(3,4,5        or 6)Me₂-Ph, —NH-2,(3,4,5 or 6)Et₂-Ph, —NH-2,(3,4,5, or        6)Pr₂-Ph, —NH-2,(3,4,5 or 6)Bu₂-Ph,    -   a substituted or unsubstituted cyclic amine or amido group (such        as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,        piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl,        3-keto-piperidinyl, and 4-keto-piperidinyl);    -   a substituted or unsubstituted cyclic C₃-C₈ alkyl group (such as        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl        and cyclooctyl);    -   an —OH group or a substituted or unsubstituted linear or        branched C₁-C₆ alcohol group (such as —CH₂OH, —CH₂CH₂OH,        —CH(CH₃)CH₂OH, —C(CH₃)₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH,        —CH(CH₃)CH₂CH₂OH, —CH(CH₃)CH(CH₃)OH, —CH(CH₂CH₃)CH₂OH,        —C(CH₃)₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, and —CH₂CH₂CH₂CH₂CH₂CH₂OH);    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid group (such as —COOH, —CH₂COOH, —CH₂CH₂COOH,        —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, and —CH₂CH₂CH₂CH₂CH₂COOH);    -   a substituted or unsubstituted linear or branched carbonyl group        (such as —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu,        —(CO)iBu, —(CO)tBu, —(CO)Ph, —(CO)CH₂Ph, —(CO)CH₂OH,        —(CO)CH₂OCH₃, —(CO)CH₂NH₂, —(CO)CH₂NHMe, —(CO)CH₂NMe₂,        —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)NH₂,        —(CO)NHMe, —(CO)NMe₂, —(CO)NHEt, —(CO)NEt₂,        —(CO)-pyrollidine-N-yl, —(CO)-morpholine-N-yl,        —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,        —(CO)NHCH₂CH₂OH, —(CO)NHCH₂CH₂OMe, —(CO)NHCH₂CH₂NH₂,        —(CO)NHCH₂CH₂NHMe, and —(CO)NHCH₂CH₂NMe₂;    -   a substituted or unsubstituted linear or branched C₁-C₆        carboxylic acid ester group (such as —COOMe, —COOEt, —COOPr,        —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH₂COOMe,        —CH₂CH₂COOMe, —CH₂CH₂CH₂COOMe, and —CH₂CH₂CH₂CH₂COOMe);    -   a substituted or unsubstituted linear or branched C₁-C₆ amide        group (such as —CO—NH₂, —CO—NMeH, —CO—NMe₂, —CO—NEtH, —CO—NEtMe,        —CO—NEt₂, —CO—NPrH, —CO—NPrMe, and —CO—NPrEt);    -   a substituted or unsubstituted linear or branched C₁-C₇ amino        carbonyl group (such as —NH—CO-Me, —NH—CO-Et, —NH—CO—Pr,        —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me,        —NMe-CO-Et, —NMe-CO—Pr, —NMe-CO-Bu, —NMe-CO-pentyl,        —NMe-CO-hexyl, —NMe-CO-Ph;    -   a substituted or unsubstituted linear or branched C₁-C₇ alkoxy        or aryloxy group (such as —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu,        —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH₂F, —OCHF₂, —OCF₃,        —OCH₂Cl, —OCHCl₂, —OCCl₃, —O-Ph, —O—CH₂-Ph, —O—CH₂-(2,3 or        4)-F-Ph, —O—CH₂-(2,3 or 4)-Cl-Ph, —CH₂OMe, —CH₂OEt, —CH₂OPr,        —CH₂OBu, —CH₂CH₂OMe, —CH₂CH₂CH₂OMe, —CH₂CH₂CH₂CH₂OMe, and        —CH₂CH₂CH₂CH₂CH₂OMe);    -   a substituted or unsubstituted linear or branched aminoalkoxy        group (such as —OCH₂NH₂, —OCH₂NHMe, —OCH₂NMe₂, —OCH₂NHEt,        —OCH₂NEt₂, —OCH₂CH₂NH₂, —OCH₂C H₂NHMe, —OCH₂CH₂NMe₂,        —OCH₂CH₂NHEt, and —OCH₂CH₂NEt₂;    -   a substituted or unsubstituted sulphonyl group (such as —SO₂Me,        —SO₂Et, —SO₂Pr, —SO₂iPr, —SO₂Ph, —SO₂-(2,3 or 4)-F-Ph,        —SO₂-cyclopropyl, —SO₂CH₂CH₂OCH₃), —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NEt₂, —SO₂-pyrrolidine-N-yl, —SO₂-morpholine-N-yl,        —SO₂NHCH₂OMe, and —SO₂NHCH₂CH₂OMe;    -   a substituted or unsubstituted aminosulphonyl group (such as        —NHSO₂Me, —NHSO₂Et, —NHSO₂Pr, —NHSO₂iPr, —NHSO₂Ph, —NHSO₂-(2,3        or 4)-F-Ph, —NHSO₂-cyclopropyl, —NHSO₂CH₂CH₂OCH₃);    -   a saturated or unsaturated, substituted or unsubstituted,        non-aromatic heterocyclic group (such as pyrrolidine-1-yl,        pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl,        piperidine-2-yl, piperidine-3-yl, piperidine-4-yl,        2-azapiperidine-1-yl, 2-azapiperidine-3-yl,        2-azapiperidine-4-yl, 3-azapiperidine-1-yl,        3-azapiperidine-2-yl, 3-azapiperidine-4-yl,        3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl,        furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl,        2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl,        2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl,        3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,        4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl,        4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl,        tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl,        2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,        2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,        3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl,        3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl,        2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl,        2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl,        2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl,        3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl,        3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl,        morpholine-2-yl, morpholine-3-yl, morpholine-4-yl,        thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl,        2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl,        2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl,        3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl,        4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl,        4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl,        thiolane-3-yl, thiane-2-yl, thiane-3-yl, and thiane-4-yl); and    -   where there are one or two R groups attached to the same atom,        they may together form a group which is double bonded to that        atom, (such as a carbonyl group (═O) or an alkene group        (═C(R′)₂) (wherein each R′ group is the same or different and is        H or an organic group, preferably H or a straight or branched        C₁-C₆ alkyl group));

preferably wherein, R³ and R⁵ may each be selected independently from:H, a substituted or unsubstituted C₁-C₆ alkyl group, an —NH₂ or asubstituted or unsubstituted C₁-C₆ amino group, a substituted orunsubstituted C₁-C₆ alkoxy group, and a nitrile group.

Thus, the present invention provides a TDO or IDO inhibitor compound foruse in medicine, which compound comprises a formula selected from one ofthe following:

Typically, the above formulae (and all formulae herein) are shown innon-stereoisomeric form. For the avoidance of doubt, throughout thepresent disclosure a single formula is intended to represent allpossible stereoisomers of a particular structure, including all possibleisolated enantiomers corresponding to the formula, all possible mixturesof enantiomers corresponding to the formula, all possible mixtures ofdiastereomers corresponding to the formula, all possible mixtures ofepimers corresponding to the formula and all possible racemic mixturescorresponding to the formula. In addition to this, the above formulae(and all formulae herein) are intended to represent all tautomeric formsequivalent to the corresponding formulae.

In the context of the present invention, the medicinal use is notespecially limited, provided that it is a use which is facilitated bythe TDO and/or the IDO inhibitory effect of the compound. Thus, thecompounds of the invention may be for use in any disease, condition ordisorder that may be prevented, ameliorated or treated using a TDOand/or IDO inhibitor. Typically this comprises a disease conditionand/or a disorder selected from: a cancer, an inflammatory condition, aninfectious disease, a central nervous system disease or disorder,coronary heart disease, chronic renal failure, post anaesthesiacognitive dysfunction, a disease condition and/or a disorder relating tofemale reproductive health including contraception or abortion, andcataracts.

When the disease, condition or disorder is an inflammatory disease,condition or disorder, it is not especially limited, provided that thedisease, condition or disorder is one which may be treated, prevented orameliorated by using a TDO and/or IDO inhibitor. However, typically theinflammatory condition is a condition relating to immune B cell, T cell,dendritic cell, natural killer cell, macrophage, and/or neutrophildysregulation.

When the disease, condition or disorder is a cancer, it is notespecially limited, provided that the cancer is one which may betreated, prevented or ameliorated by using a TDO and/or IDO inhibitor.Thus the cancer may be a cancer selected from: a solid or liquid tumourincluding cancer of the eye, brain (such as gliomas, glioblastomas,medullablastomas, craniopharyngioma, ependymoma, and astrocytoma),spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity,small intestine, colon, parathyroid gland, gall bladder, head and neck,breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung,bronchus, liver, skin, ureter, urethra, testicles, vagina, anus,laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland,pituitary gland, salivary gland, prostate, pancreas, adrenal glands; anendometrial cancer, oral cancer, melanoma, neuroblastoma, gastriccancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, apancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cellcarcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma,hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such asLhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, andProteus-like syndrome), leukaemias and lymphomas (such as acutelymphoblastic leukaemia, chronic lymphocytic leukaemia, acutemyelogenous leukaemia, chronic myelogenous leukaemia, hairy cellleukaemia, T-cell prolymphocytic leukemia (T-PLL), large granularlymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocyticleukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma,follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma,Hodgkin lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, andcutaneous T-cell lymphoma). However, when the compound is an IDOinhibitor, typically (but not exclusively) the cancer is a cancerselected from acute myeloid leukemia (AML), a small-cell lung cancer, amelanoma, an ovarian cancer, a colorectal cancer, a pancreatic cancer,an endometrial cancer, and a skin papilloma. When the compound is a TDOinhibitor, typically (but not exclusively) the cancer is a cancerselected from a glioma, and a hepatocellular carcinoma.

When the disease is an infectious disease, it is not especially limited,provided that the disease is one which may be treated, prevented orameliorated by using a TDO and/or IDO inhibitor. However, typically theinfectious disease is selected from a bacterial infection and a viralinfection, preferably a gut infection, sepsis, and sepsis inducedhypotension.

When the disease, condition or disorder is a central nervous systemdisease, condition or disorder, it is not especially limited, providedthat the disease, condition or disorder is one which may be treated,prevented or ameliorated by using a TDO and/or IDO inhibitor. However,the central nervous system disease, condition or disorder is typicallyselected from amyotrophic lateral sclerosis (AML), Huntington's disease,Alzheimer's disease, pain, a psychiatric disorder, multiple sclerosis,Parkinson's disease, and HIV related neurocognitive decline.

When the disease, condition or disorder is one relating to femalereproductive health, it is not especially limited provided that thedisease, condition or disorder is one which may be treated, prevented orameliorated by using a TDO and/or IDO inhibitor. In typical embodimentsthe disease, condition or disorder is selected from gynaecologicaldisorders such as endometriosis. Conditions relating to femalereproductive health that are included in the invention includecontraception and abortion such that the compounds of the invention maybe used as a contraceptive and/or abortive agent.

The present invention also provides a pharmaceutical compositioncomprising a compound as defined above. Whilst the pharmaceuticalcomposition is not especially limited, typically the composition furthercomprises a pharmaceutically acceptable additive and/or excipient. Inthe pharmaceutical composition, the compound as defined above may bepresent in the form described above, but may alternatively be in a formsuitable for improving bioavailability, solubility, and/or activity,and/or may be in a form suitable for improving formulation. Thus, thecompound may be in the form of a pharmaceutically acceptable salt,hydrate, acid, ester, or other alternative suitable form. Typically, thecomposition is for treating a disease, condition or disorder as definedabove. In some instances, the compound may be present in the compositionas a pharmaceutically acceptable salt, or other alternative form of thecompound, in order to ameliorate pharmaceutical formulation.

In some embodiments the pharmaceutical composition is a composition fortreating a cancer, further comprising a further agent for treatingcancer. The further agent for treating cancer is not especially limited,provided that it affords some utility for cancer treatment. However,typically the further agent for treating cancer is selected fromanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormone analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agentsand cell cycle signalling inhibitors. An immunotherapeutic agent mayconsist of but is not limited to an anti-tumour vaccine, an oncolyticvirus, an immune stimulatory antibody such as anti-CTLA4, anti-PD1,anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3,anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, achimeric antigen receptor T cell therapy (CAR-T), a small moleculeimmune modulator, tumour microenvironment modulators, andanti-angiogenic agents.

In still further embodiments the invention provides a pharmaceutical kitfor treating a cancer, which pharmaceutical kit comprises:

-   -   (a) a compound as defined above; and    -   (b) a further agent for treating cancer; preferably wherein the        further agent for treating cancer is selected from        anti-microtubule agents, platinum coordination complexes,        alkylating agents, antibiotic agents, topoisomerase II        inhibitors, antimetabolites, topoisomerase I inhibitors,        hormones and hormone analogues, signal transduction pathway        inhibitors, non-receptor tyrosine kinase angiogenesis        inhibitors, immunotherapeutic agents, proapoptotic agents and        cell cycle signalling inhibitors;        wherein the compound and the further agent are suitable for        administration simultaneously, sequentially or separately.

Further provided by the invention is a method of treating a diseaseand/or a condition and/or a disorder, which method comprisesadministering to a patient (or subject) a compound, or a composition, ora kit as defined above. The method is typically a method for treatingany disease condition or disorder mentioned herein. In typicalembodiments, the method is a method for treating a cancer. Preferablysuch a method comprises administering to a patient (or subject) acompound or a composition as defined above and a further agent fortreating cancer as defined above. The compound or composition and thefurther agent may administered simultaneously, sequentially orseparately, depending upon the agents and patients involved, and thetype of cancer indicated.

Typically, in all embodiments of the invention, both above and below,the patient (or subject) is an animal, typically a mammal, and moretypically a human.

Further provided by the invention is a method of synthesis of a compoundas defined above, which method comprises a ring closing step to form thefive-membered ring corresponding to ring Q in the compounds of thepresent invention.

In typical embodiments, this method of synthesis is carried out byreacting under conditions suitable for a condensation reaction. Theskilled person may select the reaction conditions, with reference toknown synthesis techniques depending on the appropriate startingmaterials. In some embodiments, the method comprises one or moreadditional substitution steps. The skilled person may select thereaction conditions, with reference to known synthesis techniques. Anexemplary synthesis is shown in the Examples herein.

In addition to compounds for use in medicine, the present invention, andin particular the synthetic method, provides compounds that were notpreviously known, such compounds comprising a formula selected from oneof the following:

Typically, the above formulae (and all formulae herein) are shown innon-stereoisomeric form. For the avoidance of doubt, throughout thepresent disclosure a single formula is intended to represent allpossible stereoisomers of a particular structure, including all possibleisolated enantiomers corresponding to the formula, all possible mixturesof enantiomers corresponding to the formula, all possible mixtures ofdiastereomers corresponding to the formula, all possible mixtures ofepimers corresponding to the formula and all possible racemic mixturescorresponding to the formula. In addition to this, the above formulae(and all formulae herein) are intended to represent all tautomeric formsequivalent to the corresponding formula.

The invention will now be described in more detail, by way of exampleonly, with reference to the following specific embodiments.

EXAMPLES Example 1—Methods of Synthesis

In order to demonstrate an exemplary method for synthesising thecompounds of the present invention (depicting the ring closing step forring Q), the following synthesis was carried out.

Example 2—Assays

Exemplary compounds of the invention were prepared, and tested todetermine their effect as TDO and/or IDO inhibitors. Two differentassays were employed: 1. a cell-based assay for detecting the effect oftest compounds on kynurenine production in two different cancer celltypes. This assay utilised cancer cells which expressed either TDO(A172) or IDO (SKOV3) and as such was used as a means of testingcompound activity at these two enzymes in a cell-based context. 2. a TDOand IDO biochemical coupled assay which utilised recombinantly producedand purified TDO and IDO enzymes in combination with the enzymeformamidase. This coupled enzyme system allowed conversion ofN-formylkynurenine produced by TDO or IDO activity to kynurenine whichwas then quantified by fluorescence following addition of Erhlich'sReagent The protocols for these are set out below.

Cell Based Assay for Detection of Kynurenine Produced by TDO and/or IDO

A172 (human glioblastoma) and SKOV3 (human ovarian adenocarcinoma) cellswere seeded in a 96 well plate at 30,000 or 40,000 cells per wellrespectively in phenol red-free RPMI supplemented with 10% FCS, 2 mML-glutamine and 500 M L-tryptophan. IDO expression was induced in theSKOV3 cells by the addition of 500 ng/ml IFN-γ. Cells were incubated at37° C. with or without the addition of test compound. After 48 hours,the cells were removed by centrifugation and Erhlich's reagent was addedto the supernatant. The Erhlich's reagent was incubated for 5 minutesbefore the absorbance was read at 490 nM.

TDO and IDO Biochemical Coupled Assay

Recombinant human IDO or TDO was incubated in 50 mM KPO4 (pH 7.0), 0.5mM EGTA, 0.5 mM EDTA, 0.05% Triton™ X100, 20 mM ascorbate, 10 Mmethylene blue, 500 U/ml catalase, 50 μg/ml KynB (kynurenineformamidase). TDO assays were carried out in the presence of 330 μML-tryptophan, while IDO assays had the addition of 45 M L-tryptophan.After incubation for 17 minutes at room temperature the reactions werestopped by the addition of Erhlich's reagent and incubated at roomtemperature for 5 minutes before the fluorescence was read (Ex475,Em530).

The pIC50 values for a variety of test compounds are shown in Table 1and Table 2.

TABLE 1 pIC50 values for Kynurenine cell-based assays determined fortest compounds A172 Kynurenine SKOV3 Kynurenine cell based cell basedCompound assay pIC50 assay pIC50 1 +++ ++ 2 +++ ++ 3 +++ ++ 4 ++ ++ 5+++ ++ 6 ++ +/− 7 +++ ++ 8 +/− ++ 9 ++ + 10 ++ + 11 ++ + 12 +++ ++ 13+++ ++ 14 ++ ++ 15 + ++ 16 ++ ++ 17 ++ + 18 ++ ++ 19 + ++ 20 ++ ++ 21 ++++ 22 ++ ++ 23 ++ +/− 24 ++ ++ 25 +++ ++ 26 + ++ 27 ++ ++ 28 +++ ++ 29 +++ 30 ++ + 31 +/− ++ 32 +/− + 33 + +/− 34 ++ ++ 35 ++ + 36 ++ + 37 ++ ++38 ++ + 39 + ++ 40 +++ ++ 41 +++ ++ 42 +++ + 43 +++ ++ 44 +++ ++ 45+++ + 46 ++ + 47 ++ + 48 ++ +/− 49 +++ ++ 50 ++ ++ 51 ++ ++ 52 + +++53 + ++ 54 + ++ 55 +/− + 56 +/− ++ 57 +++ ++ 58 ++ + 59 +/− + 60 ++ +61 + +/− 62 ++ ++ 63 +++ ++ 64 ++ + 65 +++ ++ 66 ++ +/− 67 +/− + 68 ++ +69 +++ + 70 ++ ++ 71 ++ + 72 +/− + 73 +++ ++ 74 + + 75 +++ + 76 ++ + 77+/− + 78 ++ + 79 +/− ++ 80 +/− + 81 +++ ++ 82 +++ + Key: +++ = pIC₅₀ ≥5.50 ++ = pIC₅₀ 4.50-5.49 + = pIC₅₀ 4.00-4.49 +/− = pIC₅₀ < 4.00 NT =not tested

TABLE 2 pIC50 values for IDO and TDO inhibition determined for testcompounds hIDO biochemical hTDO biochemical Compound assay pIC50 assaypIC50 1 ++ ++ 5 ++ + 7 ++ ++ 13 ++ + 17 + + 26 +++ +/− 34 ++ ++ 49 +/− +50 ++ NT 63 + +/− 75 ++ ++ 80 ++ +/− 81 + +/− Key: +++ = pIC₅₀ ≥ 5.50 ++= pIC₅₀ 4.50-5.49 + = pIC₅₀ 4.00-4.49 +/− = pIC₅₀ < 4.00 NT = not tested

The Tables show that a large number of the test compounds show strongTDO and IDO inhibitory function.

The invention claimed is:
 1. A compound having the following formula, ora pharmaceutically acceptable salt thereof:

wherein: X¹ is C; X³ and X⁵ may be independently selected from C and O,wherein one of X3 and X5 is C and the other is O; Y is N; each bondrepresented by a dotted line may independently be a double bond or asingle bond, provided that valencies at each ring atom are maintainedand provided that the ring Q contains at least one double bond andprovided that the atom N has a double bond; R³ and R⁵ may be present orabsent and may be the same or different and, when present, each isindependently selected from H and C₁-C₆ alkyl, provided that the numberof R³ groups present is such that the valency of X³ is maintained, andthe number of R⁵ groups present is such that the valency of X⁵ ismaintained; R²¹ is selected from H, C₁-C₆ alkyl,

wherein R²¹¹ is a group selected from: H; C₁-C₆ alkyl, unsubstituted orsubstituted with 1 to 3 substituents independently selected from —OH,C₃-C₆ cycloalkyl, —NH₂, —NH—C₁-C₆ alkyl, —N(C₁-C₆ alkyl)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)(SO₂—C₁-C₆ alkyl), —NH—SO₂—C₁-C₆ alkyl, —C(O)OH,—C(O)O—C₁-C₆ alkyl, —C(O)—NH—C₁-C₆ alkyl, phenyl, tetrahydropyranyl,piperidinyl, pyrrolidinyl and pyridinyl; C₃-C₆ cycloalkyl; phenyl,unsubstituted or substituted with 1 to 3 substituents independentlyselected from C₁-C₆ alkyl, halogen and —SO₂—C₁-C₆ alkyl; and aheterocyclic ring selected from the group consisting oftetrahydropyranyl, piperidinyl, and pyrrolidinyl, each of which isunsubstituted or substituted with 1 to 3 substituents independentlyselected from C₁-C₆ alkyl, —C(O)—C₁-C₆ alkyl and —SO₂—C₁-C₆ alkyl; R²²is selected from the group consisting of H and C₁-C₆ alkyl; and Cy is acyclic organic group selected from phenyl and pyridinyl, wherein each ofthe phenyl and pyridinyl is unsubstituted or substituted with 1 to 3substituents independently selected from C₁-C₆ alkyl, —CN, halogen, —OH,—NO₂ and —O—C₁-C₆ alkyl.
 2. The compound of claim 1 selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein Cy is phenyl, unsubstituted or substituted with 1 to 3substituents independently selected from C₁-C₆ alkyl, —CN, halogen, —OH,—NO₂ and —O—C₁-C₆ alkyl; or a pharmaceutically acceptable salt thereof.4. The compound of claim 1, wherein, where present, R³ and R⁵ are eachindependently selected from H and a linear or branched C₁-C₆ alkylgroup; or a pharmaceutically acceptable salt thereof.
 5. The compound ofclaim 1, wherein R²¹ is selected from:

wherein R²¹¹ is a group selected from: H; C₁-C₆ alkyl, unsubstituted orsubstituted with 1 to 3 substituents independently selected from —OH,C₃-C₆ cycloalkyl, —NH₂, —NH—C₁-C₆ alkyl, —N(C₁-C₆ alkyl)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)(SO₂—C₁-C₆ alkyl), —NH—SO₂—C₁-C₆ alkyl, —C(O)OH,—C(O)O-C₁-C₆ alkyl, —C(O)—NH—C₁-C₆ alkyl, phenyl and tetrahydropyranyl;C₃-C₆ cycloalkyl; phenyl, unsubstituted or substituted with 1 to 3substituents independently selected from C₁-C₆ alkyl, halogen and—SO₂—C₁-C₆ alkyl; and a heterocyclic ring selected from the groupconsisting of tetrahydropyranyl, piperidinyl, pyrrolidinyl, andpyridinyl, each of which is unsubstituted or substituted with 1 to 3substituents independently selected from C₁-C₆ alkyl, —C(O)—C₁-C₆ alkyland —SO₂—C₁-C₆ alkyl; or a pharmaceutically acceptable salt thereof. 6.A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient. 8.The pharmaceutical composition of claim 7 for treating a cancer, furthercomprising a further agent for treating cancer; wherein the furtheragent for treating cancer is selected from anti-microtubule agents,platinum coordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormone analogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents (such as an anti-tumour vaccine, an oncolyticvirus, an immune stimulatory antibody such as anti-CTLA4, anti-PD1,anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3,anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, achimeric antigen receptor T cell therapy (CAR-T), a small moleculeimmune modulator, tumour microenvironment modulators, andanti-angiogenic agents), proapoptotic agents and cell cycle signallinginhibitors.
 9. The pharmaceutical composition of claim 8, wherein thefurther agent is selected from: an anti-tumour vaccine; a cancerimmunotherapy treatment (such as an immune checkpoint modulator such asan anti-CTLA4, anti-PD1, anti PDL-1, anti-LAG3, or anti-TIM3 agent, andCD40, OX40, 41BB or GITR agonists); an immunomodulator; animmunosuppressant; a cytokine therapy; a tyrosine kinase inhibitor; anda chimeric antigen receptor T cell therapy (CAR-T).
 10. A pharmaceuticalkit for treating a cancer, which pharmaceutical kit comprises: (a) acompound of claim 1, or a pharmaceutically acceptable salt thereof; and(b) a further agent for treating cancer; wherein the further agent fortreating cancer is selected from anti-microtubule agents, platinumcoordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormone analogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents (such as an anti-tumour vaccine, an oncolyticvirus, an immune stimulatory antibody such as anti-CTLA4, anti-PD1,anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3,anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, achimeric antigen receptor T cell therapy (CAR-T), a small moleculeimmune modulator, tumour microenvironment modulators, andanti-angiogenic agents), proapoptotic agents and cell cycle signallinginhibitors; wherein the compound and the further agent are suitable foradministration simultaneously, sequentially or separately.
 11. Acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.